One objective is to identify the carcinogenic substances in betel nut and unburned tobacco. Standard extraction and purification procedures will be utilized and relative carcinogenic activity of different fractions assessed by topical application to the hamster buccal pouch. Various procedures will be utilized to enhance sensitivity of the animals to actions of the test materials. These include: 1. administration of estrogens (already shown to enhance carcinogenic activity of crude betel nut extract); 2. impairment of the immune system by: administration of antilymphocyte serum; administration of L-asparaginase combined with diets deficient in asparagine and glutamine; by administration of immunosuppressive drugs methotrexate, cyclophosphamide and vinblastine; and feeding a diet deficient in Vitamin A. Enhancing ability of each procedure will be evaluated alone and in combination. Effects of test extracts will be assessed with the light microscope. The ability to produce tumors in the buccal pouch of drugs associated with the production of tumors at other sites will be studies. Agents will include: sinapylaldehyde, N-methyl-N-nitrosourea, dioxane, and dibutylnitrosamine. The effect of excessive alcohol consumption by hamsters on buccal pouch carcinogenesis will be investigated. The involvement of the adenyl cyclase-cyclic AMP system in oral carcinogenesis will be studied by measuring changes in these substances that take place in buccal pouch tissue during tumor development initiated by betel nut extracts and other carcinogens. Ultrastructural studies with the electron microscope will be made of changes in buccal mucosa that occur during early, intermediate and late states of tumor development. Utilizing saccharated ion ocide and horseradish peroxide as electron dense markers, an ultrastructural evaluation of changes in transendothelial permeability during tumor development will be made. It is hoped to develop a model oral tumor system in hamsters similar to human oral tumors. Such a model system will be used to test effects of existing and newly developed antitumor drugs for possible usefulness in treatment of the human disease.